Alpha-tocotrienol quinone is under development for the treatment of symptoms associated with mitochondrial diseases. In vitro experiments with alpha-tocotrienol quinone have shown it to be far more potent than COQ10 in enhancing mitochondrial function. (Shrader, W. D.; et al.; Bioorganic Medicinal Chemistry Letters, 2011; 21(12):3693-3698. Preliminary studies have shown it to have some efficacy in patients suffering from mitochondrial diseases such as Friedreich Ataxia, Leigh Syndrome, and Leber's Hereditary Optic Neuropathy (See for example co-assigned U.S. application Ser. Nos. 12/777,179, 12/982,716, 12/768,565, published as US 2010/0222436, US 2011/0172312, and US 2010/0273894, respectively).
The synthesis of alpha-tocopherol quinone by oxidation of alpha-tocopherol with ferric chloride was first reported in 1937 (John, Z., Physiol. Chem., 250 (1937)). Emmerie and Engels described a procedure to use oxidation with ferric chloride as a quantitative measurement for the amount of alpha-tocopherol in materials (Emmerie and Engel, Rec. Trav. Chim., 57:135 (1938)). Skinner has described some side-products that can occur during oxidation of alpha-tocopherol (Skinner, W. A., Ph.D. Thesis, University of Texas at Austin (1952)). Robeson et al. described and claimed a procedure under improved reaction conditions to produce alpha-tocopheryl quinone free of objectionable amounts of other alpha-tocopherol oxidation products by reacting alpha-tocopherol with ferric chloride in a two-phase solvent reaction medium (U.S. Pat. No. 2,856,414).
However, traditional methods of synthesizing alpha-tocopherol quinone often result in higher than desired concentrations of side-products, mostly when commercial R,R,R-alpha-tocopheryl acetate, invariably contaminated with varying amounts of beta-tocopheryl acetate and gamma-tocopheryl acetate is used. This was disclosed in co-assigned U.S. application Ser. No. 13/044,056 (US 2011/0263720), but nowhere in this application is disclosed the use of special ratios of metal complexes added to the mixture in sequential additions, when the starting material is alpha-tocotrienol containing some non-alpha tocotrienols as impurities. It was also surprising that the oxidation of alpha-tocotrienol required a higher stoichiometric ratio of oxidizing agent than that of alpha tocopherol.
The process used in the production of alpha-tocotrienol as described in co-assigned U.S. application Ser. No. 12/606,923 (US 2010/0105930), may produce amounts of alpha-tocotrienol still containing some, although minimal, amounts of non-alpha tocotrienols that upon oxidation, might give undesirable non-alpha-tocotrienol quinones. The methods of the present invention would improve the purity of the alpha-tocotrienol quinone produced by the synthesis as described in U.S. application Ser. No. 12/606,923 (US 2010/0105930).